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This describes an as-yet unknown and unexpected effect of lithium ions as inhibitors of γ-secretase, the intramembrane proteinase responsible for the cleavage of AβPP and Notch, among other targets. Thereby, lithium reduces the Aβ levels (40 and 42!) in transfected CHO-cells in primary neurons and in mouse brain in vivo.

This effect and the data being what they are, one is left to explain them, and the authors go to great lengths to identify GSK3, but, surprisingly, not GSK3β, but GSK3α as the target in this setting. So far, the latter has not been regarded with much interest in AD, while the GSK3β variant has been a favorite of some tauists among us, if not Baptists. The results are most certainly interesting, and when confirmed, will raise many questions and follow-up studies.

First, the "unspecific" inhibition of γ-secretase by lithium ions, and by some NSAIDs, certainly makes understanding the control of γ-secretase’s specificity even more pivotal and central, and not just for AD. The "selectivity-control" mechanisms operate with regard to differentiating between distinct substrates, e.g., AβPP and Notch, at different times, e.g., in the developing and adult brain. Moreover, cleavage of the AβPP substrate renders both amyloid peptides of 40 or 42 residues (and some others); that appears to be controlled by yet other mechanisms, as implied by the current data. The multicomponent proteinase that PS1-dependent γ-secretase is will certainly show more Janus faces in the future.

Second, lithium ions appear to invoke a pronounced accumulation of AβPP-CTF, mainly of the C83 or α-stubs of AβPP (judging from Fig 1c, about a 100-fold increase). This poses a biochemical problem with pathophysiological consequences. Although adult neurons in transgenic mouse brain can do without PS1 altogether and without the larger fraction of their γ-secretase activity, the ensuing reduction in amyloid peptide levels and the elimination of amyloid plaques did not improve cognition any behavior. In fact, the opposite happened, which was attributed to the accumulated AβPP-CTF (Dewachter et al., 2002). It will be worthwhile to study the effect of treatment with lithium ions on the cognitive performance of AβPP transgenic mice!

Third, the data imply an unexpected difference, indeed an opposite effect of GSK3α and GSK3β on amyloid peptide levels, and hence on γ-secretase. Despite the soothing words in the conclusion, this must be a blow for believers in the tau-GSK3 connection. If inhibition of GSK3 had any effect on tangle pathology by reducing tau hyperphosphorylation, which is not certain (Spittaels et al., 2000) and yet to be demonstrated in vivo, its overall effect on AD pathology would be negative by increasing amyloid peptide production, as demonstrated here.

Certainly a hard one to crack. It leaves me wondering why lithium ions do what they are claimed here to do in transgenic mouse brain. Since lithium ions evidently inhibit not just GSK3α but also GSK3, this must have opposite effects on Aβ production. Does α override β ?

More questions emerge from studying these data, and only time and more experimentation will bring us answers.